Cell division is a highly dynamic process, which depends on the proper interaction of mitotic spindle microtubules (MTs) with chromosomes during mitosis. Because of the dynamic nature of mitosis, proteins involved in the process are prime targets for the development of inhibitors that can be used as antimitotic agents with a potential chemotherapeutic value.
Currently, many anti-cancer drugs used in cancer chemotherapy are antimitotic agents, such as taxanes (Paclitaxel, Docetaxel) which target tubulin, the basic component for the polymerization of mitotic microtubules and/or vinca-alkaloids, such as vinorelbine or vinblastine.
Other anti-cancer drugs are alkylating agents, such as cis-platine, DNA intercaling agents, such as doxorubicin, Topoisomerase I or II inhibitors, such as respectively camptothecin and etoposide, and RNA/DNA antimetabolites, such as 5-fluorouracil.
In addition to inhibitors aiming at MT assembly/dynamics and inhibitors targeting mitotic kinases, a new class of targets has emerged, that of kinesin based motor proteins.
Kinesins are proteins which use the free energy of ATP hydrolysis to drive intracellular movement and influence cytoskeleton organization (R. D. Vale and R. J. Fletterick, Annu. Rev. Cell. Dev. Biol. 13, 745-777 (1997)). More than 90 members of this family are known. In particular, a RNAi screen in human cells has identified at least 12 different members of such kinesin superfamily as being actively involved in cell division.
Several members of the kinesin superfamily play thus key roles in mitosis and some of them, such as MKlp2 (also known as KIF20A/RAB6KIFL/Rabkinesin-6, protein number NP_005724), are essential for cytokinesis and more particularly for the implementation of the cleavage furrow and spindle midzone formation. Cytokinesis marks the final step of mitosis and the cell cycle, leading to the production of two daughter cells endowed with a complete set of chromosomes and cytoplasmic organelles.
Many steps of cytokinesis, from cleavage furrow and spindle midzone formation, to transport of proteins to the cell division plane as well as furrow ingression are thought to be dependent on the function of different members of the kinesin superfamily, including Mitotic-Kinesin-Like-Protein-1 (MKlp1) and -2 (MKlp2), M-Phase-Phosphoprotein-1 (MPP1), human KIF4A (and its very close, with 99% identity, homologue KIF4B, both kinesin-4 family) and KIF14. Another protein is Eg5 (also known as KSP) which drives the movement of microtubules in vitro.
Inhibitors of kinesins have already been reported (R. Sakowicz et al., Science 280, 292-295 (1998)) or disclosed, notably in U.S. Pat. No. 6,489,134 and U.S. Pat. No. 6,890,933 but such inhibitors do not show a potential efficacy against MKlp2.
MKlp2 has been shown to be essential for normal cleavage furrow ingression and cytokinesis. Depletion of MKlp2 by siRNA leads to binucleated cells (K Taniuchi et al. Cancer Research 65, 105-112 (2005)). MKlp2 has also been identified as a cytoskeleton-associated proteins essential for lysosomal stability and survival of human cancer cells (L. Groth-Pedersen et al. PLoS One. 7(10), e45381 (2012)). Accordingly, it can thus constitute new target for the development of novel therapeutic strategies against cancer or diseases linked to uncontrolled and/or abnormal cell growth.
Currently, there is a lack of potent inhibitors for this member of the kinesin family that could be used as an anti-cancer agent and for which the specificity of the anti-MKlp2 activity could be sufficient to prevent off target toxicity.
The use of kinesin inhibitors in HIV infection treatment has also been reported in patent application EP 2 455 456. In addition, mitotic kinesin inhibitors are also used for treating lung disease, particularly pulmonary arterial hypertension, such as described in patent application WO 2012/009097.
The inventors have demonstrated that some derivatives of indole are selective inhibitors for MKlp2 in the publication S. Tcherniuk et al. (Angew. Chem. Int. 49, 8228-8231 (2010)) and in the patent application WO 2010/150211. However, alternative or improved inhibitors are still very useful and necessary. A new generation of inhibitors of cytokinesis may in particular be used for the treatment of cancer.